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PubMed2006

Pramipexole for the treatment of restless legs syndrome.

Restless legs syndrome (RLS) is a common disorder that is estimated to affect 10% of Americans. However, it remains largely undiagnosed and untreated by clinicians. The primary symptoms of this condition are leg discomfort or an urge to move that is temporarily relieved by movement and is worse at rest and at bedtime. RLS impacts the quality of life of the sufferer by disrupting sleep and disturbing or curtailing work and social activities. Approximately 80% of RLS sufferers also have periodic limb movements during sleep, in which repetitive leg movements fragment sleep and may result in daytime drowsiness. RLS may be treated by dopaminergic agents, benzodiazepines, anticonvulsants and opiates; dopamine agonists are currently considered first-line therapy for this condition. Pramipexole has been studied in the treatment of RLS since 1998. This article reviews the role of this medication in the management of this serious neurological disorder.

Adult↗

PubMed2002

Effects of immobility on sensory and motor symptoms of restless legs syndrome.

Restless legs syndrome (RLS) is defined by an irresistible need to move associated with leg paresthesia. Two additional features are essential for diagnosis: (1) worsening of symptoms at rest with temporary relief by activity, and (2) worsening of symptoms during the evening and/or during the night. The suggested immobilization test (SIT) has been developed to evaluate the presence of these criteria. This test quantifies leg movements and leg discomfort during a 1-hour period of immobility prior to bedtime. We used the SIT to evaluate the effects of immobility on leg discomfort and leg movements experienced by 19 patients with RLS and 19 control subjects. Results show that immobility significantly worsens both leg discomfort and periodic leg movements (PLM) in patients with RLS but not in controls. Patients with RLS showed a higher leg discomfort score (32.6 +/- 15.1 mm vs. 5.7 +/- 7.9 mm; P < 0.00001), a greater maximum leg discomfort value (63.4 +/- 27.4 mm vs. 13.7 +/- 23.0 mm; P < 0.00001) and a greater PLM index (88.4 +/- 62.6 vs. 10.4 +/- 20.6; P < 0.00004) than control subjects. These results further validate the use of the SIT as a diagnostic and research tool for RLS and confirm the contention of the International RLS study group that RLS symptoms worsen at rest.

Adult↗

PubMed2004

Epidemiology and clinical findings of restless legs syndrome.

Restless legs syndrome (RLS) is a sensory-motor disorder characterized by discomfort of and urge to move the legs, primarily during rest or inactivity, partial or total relief with movement, with presence or worsening exclusively in the evening. It is a relatively common but frequently unrecognized disorder, with a prevalence ranging from 2.5 to 15% of the general population, increasing with age and with a female preponderance. The diagnosis is clinical but polysomnography is useful to determine its profound impact on sleep (difficulties in sleep onset, maintaining sleep during the night, and sleep fragmentation) and for the evidence of periodic legs movements during sleep and wake. RLS is generally idiopathic, with familial association in 40-60% of the cases, but may also be symptomatic of such associated conditions (secondary forms) as peripheral neuropathies, uremia, iron deficiency (with or without anemia), diabetes, Parkinson's disease and pregnancy. Response to dopaminergic drugs indicates that dopamine receptors are implicated, and although much progress has been made in diagnosis and treatment in the last decade, more is needed for complete elucidation of the etiology and pathophysiology of RLS.

Adult↗

PubMed2005

Emerging drugs for restless legs syndrome.

Restless legs syndrome (RLS) is a common, but often underdiagnosed, neurological disorder, which is characterised by an imperative urge to move the extremities associated with paraesthesias, worsening of symptoms at rest and in the evening or at night, and, as a consequence, sleep disturbances. RLS affects 1-10% of the population. The aetiology of RLS is unknown, but besides genetic factors the dopaminergic and opioidergic system may play a crucial role and new developments also point to an exciting iron-dopamine connection in the pathophysiology of this burdening disorder. Due to the limited disease-specific knowledge, current treatment strategies are not curative, but nevertheless may produce an effective and lasting relief of symptoms. Although clinically based treatment has focused on levodopa, opioids and benzodiazepines for a long time, evidence-based and clinical guidelines identify dopamine agonists as a first-line treatment for daily restless legs symptoms. These substances are now in the process of registration for this indication. Ropinirole is the first dopamine agonist that has been approved by the FDA in May 2005. In addition, several promising new therapies with nondopamine profiles are under development for RLS.

Clinical Trials as Topic↗

PubMed1995

Evidence of peripheral axonal neuropathy in primary restless legs syndrome.

Restless legs syndrome (RLS) is a well-defined clinical entity characterized by an unpleasant creeping sensation arising in the legs with an irresistible need to move them. The trouble is more pronounced when the affected people lie in a prolonged rest position and try to fall asleep. It is known that RLS may be consequent to systemic disorders and to diseases affecting the central or peripheral nervous system. The International Classification of Sleep Disorders states that peripheral neuropathy should be ruled out by medical history and clinical grounds before diagnosing primary RLS (pRLS). The present study extended peripheral nerve investigation in eight consecutive pRLS patients with normal neurological examination results and showed that all patients exhibited two or more electrical, psychophysiological, and/or morphological features of peripheral axonal neuropathy. Morphometric analysis of sural nerve showed a significant reduction in myelinated fiber density and g ratio (axon diameter/fiber diameter) in the pRLS group compared with eight control biopsy specimens. These results suggest that axonal neuropathy is often present in patients with RLS. A comprehensive peripheral nerve investigation should be considered in RLS patients.

Adult↗

PubMed2006

A new look at an under-diagnosed poorly treated condition: restless legs syndrome.

Restless legs syndrome (RLS) is a common condition that is difficult to diagnose. However, once correctly diagnosed, its management is straightforward and evidence-based. The purpose of this article is to familiarise clinicians with both the symptoms and diagnostic criteria for RLS and to elucidate secondary and often curable causes of this prevalent condition. There is also a concise review of its pathophysiology and current management strategies. The authors hope this article will raise awareness of this condition among clinicians and in doing so improve the quality of life for the patients affected by it.

Dopamine Agents↗

PubMed2006

Genetics of restless legs syndrome.

Restless legs syndrome (RLS) is a common disorder, although under-diagnosed, with a prevalence of up to 15% depending on the population sampled. Familial aggregation has been widely shown since Ekbom formerly described the condition in 1960; twin studies support a genetic contribution in the development of this disorder. Molecular genetic approaches have identified three genomic regions in RLS susceptibility, however no specific mutations have yet been identified. Herein, we review the current status of genetics in RLS, providing some methodological guidelines to help future research.

Gene Frequency↗

PubMed1987

L-dopa in uremic patients with the restless legs syndrome.

Restless legs syndrome (RLS) is a poorly understood, often distressing condition that is particularly prevalent among patients with chronic renal failure. A wide variety of medications have been used to treat RLS with variable results. In order to evaluate the efficacy of carbidopa/levodopa therapy, eight consecutive uremic patients with RLS on maintenance hemodialysis were treated with doses ranging from 25/100 to 25/250 twice daily. Six of eight patients obtained satisfactory relief which has continued for 3 months follow-up. Carbidopa-levodopa appears to be an effective opinion in management of RLS in patients with chronic rental failure.

Aged↗

PubMed1998

Olfactory function in restless legs syndrome.

Restless leg syndrome (RLS) is usually idiopathic but may occur in patients with Parkinson's disease (PD). Both respond to dopaminergic medications. Whether these disorders share a common pathophysiology is unclear. Because PD is associated with a loss of olfactory function, we compared the olfactory function of patients with RLS with control and PD patients. Using the University of Pennsylvania Smell Identification Test (UPSIT), olfactory function was found to be normal in patients with idiopathic RLS and significantly reduced in patients with PD. This suggests that the pathophysiology of RLS differs from PD, and that RLS likely is not a "forme fruste" or a preclinical sign of PD.

Aged↗

PubMed2006

Is ferroportin-hepcidin signaling altered in restless legs syndrome?

Restless legs syndrome (RLS) is a neurological disorder characterized by a strong urge to move the legs. Sufferers of RLS often experience chronic sleep deprivation, due to the characteristic worsening of symptoms both when at rest and during the night. MRI data, autopsy studies, and a consistent decrease in CSF ferritin all suggest that early-onset RLS is associated with insufficient iron in the brain. In this study, we examined the relationship between the iron regulatory hormone hepcidin and RLS. Hepcidin serves as a hormone that signals iron release from cells by interacting with ferroportin. We measured the expression and concentration of pro-hepcidin in the brain and cerebrospinal fluid of both RLS patients and control individuals. In CSF, we found that pro-hepcidin levels were significantly decreased in early-onset RLS patient samples, but not in late-onset RLS patients, when compared to controls. Conversely, in neuromelanin cells, substantia nigra, and putamen, the concentration of pro-hepcidin in RLS samples is significantly increased compared to controls. Functionally, hepcidin binds to ferroportin to limit iron movement from cells. Therefore, we provide immunocytochemical evidence that ferroportin is expressed by the epithelial cells of the choroid plexus and the ependymal cells lining the ventricles. These data suggest that sites of action for hepcidin include signaling the ventricular system for movement between brain and CSF. At this time, it cannot be determined if the lower levels of pro-hepcidin in the CSF represent a compensatory response to the decreased levels of iron in the brain or a defective signaling mechanism in RLS. Nonetheless, these data support the mounting evidence that there is a biological basis for RLS and the underlying mechanism involves iron management.

Age of Onset↗

PubMed2000

Insight into the pathophysiology of restless legs syndrome.

Restless Legs Syndrome (RLS) is a disorder of sensation with a prevalence of around 2-5% of the population. Relevant to understanding the possible pathophysiological mechanism is the fact that RLS is extremely responsive to dopaminergic agents. A second issue is that iron deficiency states may precipitate RLS in as much as 25-30% of people with iron deficiency. Studies looking at basal ganglia dopaminergic function using PET and SPECT techniques have shown a decrease in binding potential for the dopamine receptor and transporter. Similar phenomena occurs in iron-deficient animals. Using MRI techniques and CSF analysis of iron-related protein, studies have suggested a reduction in brain iron concentration occurs in RLS patients. The relevance of CNS iron metabolism to the pathophysiology of RLS is discussed.

Animals↗

PubMed2007

Controversies and challenges in defining the etiology and pathophysiology of restless legs syndrome.

Restless legs syndrome (RLS) can occur as a primary disorder, with no apparent cause other than a possible genetic predisposition, or as a secondary condition, most commonly related to iron deficiency, pregnancy, or end-stage renal disease. Recent studies have identified 2 different phenotypes of RLS based on age at onset of symptoms. Persons whose RLS symptoms start at an earlier age (<45 years) are more likely to have a family history of RLS and tend to have a more slowly progressive development of the disorder compared with individuals who have later onset of symptoms. In the past, our ability to determine either prevalence or population factors associated with increased occurrence of RLS has been limited. However, 4 different diagnostic criteria have been established. Familiarity with diagnostic criteria and clinical characteristics are essential for diagnosis and appropriate treatment, if required.

Central Nervous System↗

PubMed2005

New paradigms in the treatment of restless legs syndrome.

Restless legs syndrome (RLS) is a common neurologic disorder occurring in 3% to 15% of the general population, which contributes to poor quality of life. Many patients go undiagnosed for years after onset of symptoms, which delays or prevents effective treatment. Extensive research over the past decade has led to a better understanding of RLS and effective treatment options. This review encompasses the most recently published pathophysiology, epidemiology, criteria for diagnosis, and clinical drug efficacy trials to provide clinicians with the information to effectively manage RLS. A comprehensive review of the medical literature was conducted and original research articles pertaining to RLS were evaluated. The pathophysiology of primary RLS is associated with dopaminergic dysfunction and abnormal brain iron metabolism. Secondary RLS is most often a consequence of iron deficiency. The prevalence of primary RLS is twofold greater in women and increases with age in men and women, although onset of symptoms may occur in up to 45% of patients before age 20 years. Patients may present with a variety of complaints including sleep disruption. Several studies have demonstrated the efficacy of low-dose levodopa and dopamine agonists. Ropinirole is the most widely studied. Other drugs that may help control symptoms include gabapentin, opioids, and clonazepam. Clinicians must be aware of the high prevalence of RLS, the potential for onset before age 20, and the various clinical presentations. Dopamine agonists are first-line therapy and provide symptom relief in 70% to 100% of patients.

Brain↗

PubMed2001

Restless Legs Syndrome.

Restless Legs Syndrome (RLS) is a well-defined symptom complex and is frequently associated with sleep disturbance and a recognized family history. It occurs either as idiopathic RLS or in association with many medical, neurological or vascular disorders. The neurological examination and routine investigations in idiopathic RLS are normal. Polysomnography supports the diagnosis of RLS by documenting the associated sleep disturbances and periodic limb movements in sleep (PLMS). Although MRI studies disclose no intracerebral lesions, recent Positron Emission Tomography (PET) and single photon emission computed tomography (SPECT) studies point to some involvement of the basal and red nuclei and the cerebellum. No definitive etiology is known for this condition, but several pathophysiological mechanisms have been proposed. There is supportive evidence that RLS is a Central Nervous System (CNS) dysfunction, suggesting widespread involvement of the descending dopaminergic (DA) pathways, possibly originating in the diencephalon or upper brainstem. This is corroborated by the successful treatment of RLS with DA agents, sedatives, and neurotransmitters. However, RLS can also occur with spinal disorders and spinal cord lesions implying the existence of a spinal generator. The incidence of RLS in pregnancy is well known and its association with vascular disorders supports another mechanism in some patients. The primary treatment of RLS is largely symptomatic and quite effective with DA agents, DA agonists, opioids and other neurotransmitters. The treatment of RLS associated with various diseases is aimed at the correction of the underlying pathological or deficiency states. Antidepressant medications frequently precipitate or worsen the condition of RLS.

Adolescent↗

PubMed2006

Ferritin subunits in CSF are decreased in restless legs syndrome.

Restless legs syndrome (RLS) is a neurological disorder that may be related to iron misregulation at the level of the central nervous system. Evidence that iron is involved in RLS comes from magnetic resonance imaging data, autopsy studies, analyses of cerebrospinal fluid (CSF), and correlations of symptoms with serum ferritin. To further examine the possibility that brain iron status is insufficient in RLS, we determined ferritin levels in the CSF. Specifically, we differentiated between the H- and L-subunits of ferritin, because these peptides are expressed from different chromosomes and have different functions. We measured H- and L-ferritin subunit levels in control and RLS human CSF using immunoblot analysis and found that both H- and L-ferritin are significantly decreased in early but not late-onset RLS. Additionally, we quantified total protein in each CSF sample to establish that the decrease in ferritin subunits in RLS did not reflect a decrease in total protein in CSF. Furthermore, we used equal amounts of total CSF protein in the immunoblot analyses, in contrast to previously published studies that provided only volumetric data, to determine which approach was more accurate for quantifying the amount of ferritin relative to other proteins in CSF. Our results establish a protein standard in RLS, provide a comparative analysis of protein-controlled versus volumetric immunoblot techniques, and argue for a profound loss of iron storage capacity in the brain in RLS, specifically in the early onset RLS phenotype. These data suggest that CSF ferritin levels may provide a biomarker for assisting in the diagnosis of RLS.

Age of Onset↗

PubMed2006

Evidence for further genetic locus heterogeneity and confirmation of RLS-1 in restless legs syndrome.

Restless legs syndrome (RLS; MIM 102300) is a common neurological disorder characterized by dysesthesias and an urge to move the lower limbs. The symptoms predominantly occur at rest, in the evening, and improve with movement. There is a high familial aggregation but gene mutations have not yet been found. Three loci for RLS on chromosomes 12q, 14q, and 9p (RLS-1, RLS-2, and RLS-3) have been reported with a recessive (RLS-1) and autosomal dominant (RLS-2, RLS-3) mode of inheritance, respectively. The overall contribution of these loci to this disorder is not known. To evaluate the significance of these loci, we investigated 12 RLS families for possible linkage to these chromosomal regions. Genotyping was carried out in 70 affected family members using 26 polymorphic microsatellite markers (chromosome 12: 7; chromosome 14: 7, chromosome 9: 12). Linkage analysis was carried out using the published parameters applied in the original studies (chromosome 12: q=0.25, f0=0.005, f1=0.005, f2=0.8; chromosome 14: q=0.003, f0=0.005, f1=f2=0.95; chromosome 9: q=0.001, f0=0.005, f1=f2=0.95; affected individuals only). In addition, transmission disequilibrium test (TDT) analyses were done. We found evidence for linkage on chromosome 12 using the TDT. Linkage to RLS-2 and RLS-3 was excluded in 1 of 12 families. This supports the existence of RLS-1 and provides evidence for the likelihood of further genetic locus heterogeneity of RLS. Investigations in additional RLS families are required to confirm the known loci and further genome wide linkage analyses have the potential to identify additional RLS loci.

Adolescent↗

PubMed2001

Hemochromatosis and iron therapy of Restless Legs Syndrome.

Restless legs syndrome (RLS) occurs in some persons with iron deficiency, and some persons with RLS benefit from oral iron therapy. Approximately one in 200 persons of northern European ancestry have hemochromatosis attributable to inheritance of two common mutations of the hemochromatosis-associated HFE gene on chromosome 6. We evaluated and treated a 46-year-old man with RLS who was diagnosed as having hemochromatosis after he developed new symptoms associated with taking iron therapy for RLS. He had transferrin saturation 88%, serum ferritin 658 ng/ml, and C282Y homozygosity. Therapeutic phlebotomy of one unit of blood (450-500 ml) weekly (total 24 units) relieved his non-RLS symptoms, caused RLS symptoms to occur more frequently, and was associated with transient fatigue and mild dependent edema. His sister, who also has RLS, was subsequently diagnosed as having hemochromatosis. We conclude that serum transferrin saturation and ferritin levels should be measured before initiation of iron therapy of RLS. Patients with a history of iron deficiency or low serum iron parameters should undergo evaluation for iron deficiency; patients who have histories suggestive of hemochromatosis or iron overload or elevated pre-treatment transferrin saturation or serum ferritin levels should undergo evaluation to determine the cause of these abnormalities before they are treated with iron. In all persons with RLS treated with oral iron, serum iron parameters should be re-measured once or twice yearly during therapy.

Journal Article↗

PubMed2002

Sleep disorders. Obstructive sleep apnea syndrome, restless legs syndrome, and insomnia in geriatric patients.

Sleep disorders may affect one out of two older Americans and may present as insomnia, excessive daytime sleepiness, or both. Age-related changes seem to cause a decreased need for sleep. The average 70-year-old sleeps only 6 hours a night, but may obtain an additional hour or even 2 during daytime naps. Older adults also experience an increase in the number of sleep disruptions and an increased incidence of chronic diseases, which can contribute to poorer sleep in this group. The two most common geriatric sleep disorders are obstructive sleep apnea syndrome and restless legs syndrome. Detailed diagnostic workup and treatment are usually referred to a center for sleep medicine where polysomnographic studies are performed. Left untreated, sleep disorders may present a serious threat to the patient's health and lead to increased morbidity and mortality.

Age Factors↗